WO2010086484A1

WO2010086484A1 - Use of derivates of 6-substituted 3-phenylcoumarins and preparation of new derivates

Info

Publication number: WO2010086484A1
Application number: PCT/ES2010/070046
Authority: WO
Inventors: Lourdes SANTANA PENÍN; Francisco Orallo Cambeiro; Dolores VIÑA CASTELAO; Maria Joao Correia Pinto Carvalho De Matos; Elias Neftalí QUEZADA GONZÁLEZ; Matilde YAÑEZ JATO; Santiago Vilar Varela; Eugenio Uriarte Vilares
Original assignee: Universidade De Santiago De Compostela
Priority date: 2009-01-27
Filing date: 2010-01-27
Publication date: 2010-08-05
Also published as: ES2343347A1; ES2343347B2

Abstract

The present invention is directed at the use of compounds of formula I, being derivatives of 3-phenylcoumarins substituted in position 6, for the preparation of medicaments for treating disorders deriving from hyperactivity of the MAO-B isoform, such as degenerative disorders of the central nervous system or obesity. Furthermore it is directed at the preparation of certain compounds of formula I which present high activity and the use thereof.

Description

USE OF DERIVATIVES OF 3-PHENYLCUMARTNAS 6-REPLACED AND PREPARATION OF NEW DERIVATIVES

Technical sector

The present invention is directed to the use of compounds of formula I, which are derivatives of 3- phenylcoumarins with substitution in position 6, for the preparation of medicaments for treating disorders derived from the hyperactivity of the MAO-B isoform, as disorders Degenerative central nervous system or obesity. It is also aimed at the preparation of certain compounds of formula I that have high activity and their use.

State of the art Regarding biological aspects, monoamine oxidases (MAO) are a heterogeneous superfamilium of flavoenzymes that catalyze the deamination of neuro transmitters and exogenous amines. The two isoforms called MAO-A and MAO-B have been identified based on their amino acid sequence, their three-dimensional structure and the preference for certain specific substrates and inhibitors [Proc. Nati Acad. ScL USA 102, 12684-9, (2005); Proc. Nati Acad. Sci. USA 100, 9750-5, (2003)]. Thus, MAO-A has a higher affinity for serotonin or 5-hydroxytryptamine (5-HT), adrenaline (A) and norepinephrine (NA) while MAO-B preferentially deaminates β-phenylethylamine and benzylamine. These properties determine the clinical importance of MAO inhibitors [Cun: Mcd. Chem. 1 1, 2033-43. (2004)]. Selective MAO-A inhibitors (iMAO-A) such as clorgiline or moclobemide are used in the treatment of neurological disorders such as depression, while selective iMAO-B, such as i? - ^ - deprenyl (hereinafter) selegiline) and rasagiline. They are useful and authorized in Spain for the treatment of Parkinson's disease. Alzheimer's disease (AD), neurodegenerative and progressive, is the most common cause of senile dementia. Although it has a multiple etiology, it seems to be mainly due to the accumulation of β-amyloid plaques (βA) in the brain, or which can promote the degeneration or atrophy of cholinergic neurons, mainly in the cerebral cortex and in the hippocampus. Consequently, the use of acetylcholinesterase inhibitors [CNS Drugs, 12, 307-23, (1999)] has been classically used for pharmacological treatment. At present, however, new expectations are being generated by taking into account other aspects related to the etiology of the disease such as the decrease in the levels of dopamine, norepinephrine and 5-HT, or the increase in MAO- activity. Brain B which causes an increase in free radicals, responsible for oxidative stress and cell death, as well as the development of β-amyloid plaques in patients with

Alzheimer's Although further studies are required for clarification, it is believed that the beneficial effect of selective MAO-B inhibitors such as selegiline is due to a double reduction effect on free radical formation [Neurotoxicology 25, 271-7, ( 2004)] and increased levels of monoamines in the brain of these patients.

However, the main therapeutic application of iMAO-B is the treatment of Parkinson's disease (PD), a chronic and progressive neurodegenerative disorder, characterized by a predominantly motor symptomatology almost always accompanied by non-motor symptoms such as depression and anxiety, and that it is due to a decrease in the levels of dopamine in the striatum due to progressive death of nigrostriated neurons. And although classical therapy of this disease has predominantly resorted to the administration of L-dopa (associated with a peripheral DOPA decarboxylase inhibitor) and dopamine agonists, more recently new therapeutic alternatives have appeared such as COMT inhibitors. (entacapone) and that of selective MAO-B inhibitors, of which selegiline [Neurolυgy 66, 1200-6, (2006)] and ia rasagiline [Am. J. Geriatr. Pharmacother 4, 330-6, (2006)].

Regarding chemical aspects, during the last decades a high number of derivatives of 2H-1-benzopyran-2-one (hereinafter coumarin) have been synthesized whose biological activities depend on the nature and position of the substituents on said ring.

Various coumarin derivatives have been identified as inhibitors of different enzymes with potential application in neurodegenerative diseases. Thus, in 2006, the inhibitory activity of various 3-carboxamido coumarins on α-secretase and its potential use in the therapy of AD was described [J. Med. Chem. 49, 4275-85, (2006)]. In the same year, various sulfoxycoumarins were synthesized that appear to be useful in the treatment of various pathologies related to oxidative stress and / or inflammatory reactions [WO2006002918].

However, the pharmacological activity of coumarins most directly related to the present invention is its application in Parkinson's disease derived from its MAO-B inhibitory action. WO2006138475, WO2001012176 describes the preparation of coumarin analogues MAO-B inhibitors useful in the treatment of obesity or diabetes, as well as in cardiometabolic disorders such as hypertension. However, in addition to these therapeutic uses, the potential application of the iMAO-B activity of certain coumarins in the treatment of neurodegenerative diseases has been studied, study whose results in many cases have been the subject of patent applications. So, in J.

Med. Chem. 49 _; 4912-25, (2006), EP594036, DE 3834860 or DE 3834861 the structures of the coumarins studied have aryl- or heteroarylalkoxy groups on position 7 of said ring. In WO2006102958 7-substituted 4-araino and amido-alkyl coumarins are prepared. Because both the nature and the position of the substituents on the coumarin ring directly influence the biological activity of this lipo of compounds, the effect of a phenyl substituent at position 3 was studied. In this regard, researchers have demonstrated the interesting vasodilator and platelet antiaggregant activity that have various polyhydroxylated 3-phenylcoumarins related to resvcratrol [Biorg. Med. Chem. LeIt. 16, 257-61, (2006), QSAR Comb. ScL 26, 317-32, (2007)]. The selective interaction of some 3-phenyl derivatives with β-estrogenic receptors and their beneficial effect in the treatment of disorders related to estrogen replacement therapy (ERT) such as anxiety, depression, osteoporosis, prostate cancer have also been described. or the improvement of cognitive function in Alzheimer's patients [WO2002030407]. On the other hand, J. Med. Chem. 46, 2279-82, (2003) describes a 3- arylsubstituted curarynin, the first compound with a dual activity inhibiting human acetylcholine and in turn inhibiting the aggregation of β plaques -amiloids, which is why it has been revealed as a beneficial compound in AD therapy.

The present invention provides studies of activity against the MAO-B enzyme of derivatives with a 3-phenylcumarinic structure substituted at position 6, characteristics that confer greater inhibitory activity and high selectivity compared to other derivatives described.

Description of the invention

The present invention is directed to the use of a compound of formula L, for the preparation of a medicament for treating disorders derived from the hyperacidity of the MAO-B isoform,

where,

R2 ', R3', R4 ', R5' and R6 'are identical or different, each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkyloxy. acyloxy, acyl or nitro,

R4 is hydrogen, R5, R7 and R8 are identical or different, each independently selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkyloxy, acyloxy, acyl, aethylmethoxy, alkylsulfonyloxy, arylsiphenyloxy or nitro,

R6 is selected from halogen, alkyl, haloalkyl, hydroxyl, cycloalkyloxy, alkyloxy, acyloxy, acyl, acylalkyloxy, alkylsulfonyloxy, arylsulfonyloxy or nitro. In a particular aspect the compounds of formula I are selected from those where R2 ', R3', R4 ', R5' and R6 'are identical or different, each independently selected from hydrogen, halogen, hydroxy, or alkyloxy.

In a particular aspect the compounds of formula 1 are selected from those where R 6 is halogen, alkyl or haloalkyl. In another particular aspect, the compounds of formula I are selected from those where

R3 'and R4' at least one of them is halogen and the other is selected from hydrogen and alkyloxy,

R4, R5, R7, R8, R2 ', R5'and R6' are hydrogen,

R6 is alkyl or alkyloxy, preferably methyl or methyloxy. In an even more particular aspect the compounds of formula 1 are selected from:

(1) 3-Phenyl-6-methylcuntarine

(2) 6-Methyl-3- (4'-methoxy) phenylcoumarin

(3) 6-methyl-3- (3 ', 5' -dimethoxy) phenylcwnarine (4) 6-methyl-3- (3 ', 4', 5 '-trimethoxy) phenylcoumarin

(5) 3-Í4 '-hydroxy) feml-6-methylcumarwa

(6) 6-cloιv-3- (2 '-hydroxyijphenylcoumarin

(7) 6-Chloro-3- (3'-Hydroxy) Phenicicmarine

(8) 6-Chloro-3- (4'-hydroxy) phenylcoumarin (9) 6-brυmo-3- (2'-hydroxy) phenylcoumarin

(10) 6-Bromo-3- (3'-hydroxy) phenylcoumarin

(11) 6-Hromo-3- (4'-hydroxy) phenylcoumarin

(12) 6-bromυmethyl-3-phenylcoumarin

(13) 3- (3 '-bromo-4' -methoxy) feml-6-methylcumaήna (14) 8-bromo-3-feml-6-methylcumarin

(15) 8-Bromo-6-methyl-3- (4 '-methoxy) phemlcumarine

(16) 8-Bromo-6-methi-3- (3 ', 5' -dimethoxy) phenylcoumarin

(27) 3- (3 '-bromυ) phenyl-6 methylcoumarin

(28) 3- (4'-bromine) phenyl-6 methylcoumarin (35) 3- (3'-bromine) phenyl-6 tnethoxycoumarin

In a particular aspect, the disorders derived from the hyperactivity of the MAO-B syndrome are degenerative disorders of the central nervous system or obesity. These degenerative disorders are Paikinson, Alzhcimer, schizophrenia, senile dementia or ataxia.

The present invention also provides synthetic methods for obtaining the compounds of formula 1, and their pharmaceutical compositions.

Detailed description of the invention

As previously mentioned, the invention is directed to the use of the compounds of formula I for the preparation of a medicament for treating disorders derived from the hyperactivity of the MAO-B isoform.

The invention also provides new compounds of formula I, which have a high degree of effectiveness in in vitro assays inhibiting the MAO-B isoform in the nanomolar-picomolar range. In addition, these compounds have a high degree of selectivity not modifying the enzymatic activity of MAO-A. This inhibitory activity makes these compounds very useful for the preparation of a medicament for treating disorders derived from the hyperactivity of the MAO-B isoform, such as degenerative disorders of the central nervous system, such as, for example, Parkínson, Alzheimer, schizophrenia, senile dementia or ataxia; or obesity

For this reason, in a particular aspect, the invention is directed to the compounds of formula I where

R3 'and R4' at least one of them is halogen and the other is selected from hydrogen and alkyloxy, R4, R5, R7, R8, R2 ', R5'and R6' are hydrogen,

R6 is alkyl or alkyloxy, preferably methyl or methyloxy.

In an even more particular aspect, the invention is directed to the compounds of formula I selected from:

6-methyl-3- (3 ', 5' -dimethoxy) phenylcoumarin (3) 6-methyl-3- (3 ', 4', 5'-trimethoxy) phenylcumarine (4)

3- (4 '-hydroxy) feni! -6-methylcumarirta (S)

6-c / gold-3- (3'-hydroxy) phenylcwnarine (7)

6-Bromo-3- (3'-hydroxy) phenylcoumarin (10)

6-brυmo-3- (4 '-hydroxy) fenUcumaιina (11) 6-bromomethyl-3-jenylcoumarin (12)

3- (3 '-brυmo-4' 'methoxy) phenyl-6-meti? Cumaήna (13)

8-Bromo-3-phenyl-6-methylcoumarin (14)

S-Bromo-6-methyl-3- (4 '-methoxy) phenylcumarma (15)

8-Bromo-6-methyl-3- (3 ', 5' -dimethoxy) phenylcoumarin (16) 3- (3 '-bromo) phenyl-6 me H-coumarin (27)

3- (4 '-bromo) phenyl-6 methylcoumarin (28)

3- (3 '-hromo) phenyl-6 tnetylυxycoumarin (35)

In another more preferred aspect it is directed to a pharmaceutical composition comprising a compound of those listed in the above list. The compounds of formula 1 can be prepared by a Perkin reaction between the compounds of formula II (salicylaldehydes) and of formula III (phenylacetic acids), wherein R5, R6, R7, R8, R2 ', R3', R4 'and R5' they are as described above for the compounds of formula I. Preferably the reaction is carried out in the presence of an agent that favor coupling such as dicyclohexylcarbodiimide (DCC), hydroxybenzotriazole, Bates reagent, l-ethoxycarbonyl-2-ethyloxy-1,2-dihydroquinoline, carbonyldiimidazole or 1-isobutoxycarbonyl-2-isobutoxy-1,2-dihydroquinoline.

The salicylaldehydes of formula II and the 3-phenylacetic acids of formula III are commercially available compounds or can be obtained by simple transformations and of general knowledge in chemistry.

For the preparation of the compounds of formula I where R8 is halogen it is possible to carry out a haiogenation reaction in the presence of a halogenating agent such as bromine, iodine, N-bromosuccinimide, N-iodosuccinimide, POC13, tetrabromocyclohexadienone, tetralkylammonium tribromide, Hexamethylenetetramine tribromide on the starting salicylaldehyde. However, in order to obtain the halogenated derivatives on the phenyl at position 3 or by presenting haloalkyl at position 6, the haiogenation is carried out on the corresponding non-halogenated compound of formula I.

The preparation of the compounds of formula 1 wherein R 6 or R 3 'is an acylalkyl or cycloalkyloxy group is carried out by an alkylation reaction of the corresponding hydroxy derivatives with the halo derivatives of acylalkyl or cycloaquyl in the presence of anhydrous potassium carbonate, using conditions known in organic chemistry (Advanced Organic Chemistry, J. March, Ed. Wiley),

PHARMACEUTICAL PREPARATIONS

The compounds of general formula (I) included in the present invention may be contained in pharmaceutical forms for administration by means of usual processes using auxiliary substances such as liquid or solid materials. The pharmaceutical compositions of the invention can be administered orally or parenterally (via intramuscular or intravenous) in the form of solutions, powders, tablets, tablets, capsules

(including microcapsules), etc. Pharmaceutically acceptable excipients for such formulations are liquid or solid fillers and diluents, solvents, lubricants, emulsifiers, condiments, coloring substances and / or pH regulators. Optionally, it is possible to use auxiliary substances, such as magnesium carbonate or stearate, titanium dioxide, polyvinyl pyrrolidone, lactose, mannitol and other sugars or alcohols derived from sugars, talc, lactoproteins, gelatins, starch, cellulose and their derivatives, vegetable and animal oils such as fish liver oil, sunflower, walnut or sesame oils, polyethylene glycol and solvents such as, for example, distilled water and mono- or polyhydric alcohols such as glycerol.

PHARMACOLOGICAL METHODS

DETERMINATION OF THE ACTIVITY OF THE MAO ISOFORMS The effects of the compounds of formula 1 on the activity of monoamine oxidase were determined by measuring the production of hydrogen peroxide (H ₂ O ₂ ) and, consequently, of resorrufina from / j-tyramine, using the Amplex ^® Red reagent (Molecular Probes, Eugene, Oregon, USA) and the MAO isoforms present in the microsome fraction! prepared from insect cells (BTI-TN-5B1-4) infected with recombinant baculoviruses containing human MAO-A or MAO-B cDNA inserts (Sigma-Afdrich Química SA, Alcobendas, Spain).

The MAO has two different isoenzymes, the MAO-A and the MAO-B, which catalyze the oxidation of various substrates containing amino moieties to originate the corresponding aldehydes, ammonia and HoOj. I .a /> - tyramine, which is oxidized to hydroxyphenylacetaldehyde, is a common substrate for MAO-A and MAO-B. 5-HT and NA, however, are preferably oxidized by MAO-A while benzylamine and β-phenylethylamine are preferably transformed by MAO-B [Curr, Medβ. Chem, 5, 137-62 (1998), Prog. Nucleic Acid Res. Mol. Biol. 65, 129-38, (2001), Curr. Med. Chem, 1 1, 1983-93 (2004)] (see also state of the art, biological aspects). The production of H ₂ O ₂ catalyzed by the MAO isophoreas can be detected by using the Amplex ^® Red reagent (10-acetyl-3,7-dihydroxyphenoxazine), a highly sensitive, non-fluorescent substance that reacts with H2O2 in presence of horseradish peroxidase to produce a fluorescent product, resorrufina. In our experiments, the activity of the MAO was evaluated with the method mentioned above, following the general procedure previously described in Biochem, Biophys. Res, Comm. 344, 688-695, (2006) with some modifications.

First, 0.1 ml of sodium phosphate buffer (0.05 M, pH 7.4) containing different concentrations of the new compounds under study (or the reference inhibitors) and the amount of MAO-A or Human recombinant MAO-B required to obtain in our experimental conditions the same reaction rate in the presence of both isoenzymes, that is, to oxidize (in the absence of drugs: control group) the same substrate concentration: 165 pmoles of p-tyramine per minute (MAO-A: 1.1 μg; specific activity: 150 nraoles of p-tyramine oxidized to p-hydroxyphenylacetaldehyde per minute per mg of protein; MAO-B: 7.5 μg: specific activity: 22 nmoles dep-tyramine transformed per minute per mg of protein). Said incubation was carried out for 15 minutes at 37 ° C in 96-well black and flat bottom plates (Microtest ™ piate, BD, Franklin Lakes, NJ, USA), already placed in the dark chamber of the fluorescence reader ( see the model below). After the incubation period, the reaction was started by adding (final concentrations) 200 μM of Amplex ^® Red reagent, 1 unit (U) / ml of horseradish peroxidase and 1 mM of p-tyramine as a substrate, both for studies with the MAO-A as for those made with the MAO-B. The production of H ₂ O ₂ and, consequently, of resorrufina was quantified at 37 ° C in a plate fluorescence reader (FLX800 ™, Bio-Tek ^® Instruments, Inc., Winooski, VT, USA) determining The fluorescence generated (excitation 545 nm, emission 590 nm) for 15 minutes, a period in which the increase in fluorescence was linear from the beginning. Simultaneously control experiments were carried out replacing the compounds of formula I with the appropriate dilutions of the vehicles. In addition, the possible ability of the drugs to modify the fluorescence generated in the reaction mixture by a non-enzymatic inhibition (for example, by direct reaction with the Amplex Red reagent), was evaluated by adding these compounds of formula I and the reference inhibitors to solutions containing only the Amplex ^® Red reagent in sodium phosphate buffer. The specific fluorescence emission (used to obtain the final results) was calculated after subtracting the background activity, determined in vials in which the solutions with the MAO isoforms were replaced by sodium phosphate buffer solution. PRESENTATION OF DATA AND STATISTICAL ANALYSIS

Unless otherwise indicated, the results shown in the text and in the tables are expressed as the mean ± standard error of the mean (e.e.m.) of five experiments. The statistically significant difference between two means (P <0.05 or P <0.01) was determined by one-way analysis of variance (ANOVA), followed by Dunnett's multiple comparison test.

To study the possible effects of the compounds of formula I and of the reference inhibitors on the enzymatic activity of the isoforms of the MAO, the fluorescence variation was evaluated per unit time [quantified as arbitrary fluorescence units / minute] e, indirectly, the production of H ₂ O ₂ and, consequently, the pmoles / min of resorrufϊna produced in the reaction between the H ₂ O ₂ and the Amplex * Red reagent. For this, several resorrufina concentrations were used to make a curve standard, where X = pmoles of resorrufina and Y - arbitrary units of fluorescence. The resorrufina pine trees produced are equivalent to the oxidized / j-tyramine pmoles _* since the stoichiometry of the reaction is 1: 1.

In these experiments, the IMAO activity of the compounds of formula 1 and of the reference inhibitors was expressed as IC50, that is, as the concentration of each compound necessary to produce a decrease in the control value of the enzymatic activity of the isoforms of the 50% MAO. The corresponding CUo values for each compound were calculated, using the Origin ™ 5.0 software (Microcal Software, Inc., Northampton, MA, USA), from the equations of the straight lines obtained by linear regression (method of the least squares) of the resulting points when representing the log of the molar concentration of the compound studied (abscissa axis) versus the percentage of inhibition of the control MAO activity achieved with the corresponding concentrations of each compound (ordinate axis). This linear regression was performed using the data obtained with 4-6 concentrations of each compound evaluated capable of inhibiting the control enzyme activity of MAO isoenzymes between 20% and 80%. In addition, the ratio [CI $ o (MAO-A)] / [CZ ₅₀ (MAO-B)] was calculated as an indicator of the selectivity in the inhibition shown on both isoforms.

Drugs and chemical compounds evaluated

The drugs and chemicals used in the experiments were the compounds of formula I, moclobemide (kindly supplied by the Hoffman-La Roche laboratories, Basel, Switzerland), selegiline and iproniazide phosphate (purchased from Sigma-Aldrich, Spain), resoiτufina sodium salt, clorgiline hydrochloride, pyrininine hydrochloride, sodium phosphate and horseradish peroxidase (supplied in the MAO Arnplex ^® Red Molecular Probes MAO test kit).

Appropriate dilutions of the aforementioned compounds were prepared in Milli-Q ^{® water} (Millípore Ibérica S. A ,, Madπd, Spain) every day before, from use of the following concentrated stock solutions maintained at -20 ° C : the compounds of formula 1 (0.1 M) in dimethylsulfoxide (DMSO, Sigma-Aldrich); selegiline, moclobemide, iproniazide, resorrufina, clorgilina, p-tyramine and horseradish peroxtdasa (0.1 M) in Milli-Q * water.

Due to the photosensitivity of some substances used (for example, the reagent

Amplex ^® Red), all experiments were performed in the dark. In none of the trials, neither Milli-Q ^{® water} nor the vehicle used (DMSO) had a significant pharmacological effect.

The compounds of formula 1 evaluated are:

where R4, R5, R7 and R6 'are hydrogen, and OCp is cyclopentyloxy.

PHARMACOLOGICAL RESULTS AND COMPOSITE FORMULATION

The Cl ₅₀ values of the compounds of general formula (I), detailed above, are shown in Table 1.

Table 1. Selectivity ratio for MAO-B [Cl ₅₀ (MAO-A) / Cl ₅₀ ) (MAO-B)] and IC ₅₀ values of the inhibitory effect of the drugs studied (including reference inhibitors) on activity Enzymatic of the isoforms of human recombinant MAO.

The results are the mean ± eem of five experiments Level of statistical significance: ^at P <0.01 with respect to the corresponding value of Cl ₅₀ obtained against the MAO-

B, determined by the ANOVA / Dunnett test.

* Inactive at 1 mM (highest concentration studied). At higher concentrations, moclobemide precipitates.

** Inactive at 100 (highest concentration studied) At higher concentrations, the compounds precipitate. *** At the concentration of 100 μM the compound inhibits MAO-A approximately 40-

Four. Five%. At higher concentrations, the compound precipitates. bValue calculated considering as Cl ₅₀ against the MAO-A the highest concentration studied (100 μM). cValue calculated considering as Cl ₅₀ versus the MAO-B the highest concentration studied (1 mM).

Compound 13 was more effective than selegiline in decreasing the activity of MAO-B since the corresponding value of Cl ₅₀ was of the order of 30 times lower (see table 1). In addition, the selectivity of compound 13 to inhibit MAO-B was markedly superior to that exhibited by selegiline (selectivity ratio for MAO-B [Cl ₅₀ (MAO-A) / IC ₅₀ (MAO-B)]: 135,870 and 3,431, respectively) (see table 1).

On the other hand, some of the other compounds studied (2, 3, 15 and 16) were also more active and more selective than selegiline as MAO-B inhibitors (table 1), which makes them useful in the treatment of neurodegenerative disorders, preferably in Parkinson's disease.

In another aspect, the present invention provides pharmaceutical formulations for the preparation of a medicament with the compounds of formula I for the prevention and treatment of Parkinson's related disorders. The doses in which the most active compounds could be administered vary within a wide limit, adjusting to the requirements of each particular case. In general, the effective dose for oral or parenteral administration may be between 15 ng / kg / day and 150 mg / kg / day, with a dose of 150 ng / kg / day and 15 mg / being preferred for all the indications described. kg / day The daily dose for a human adult weighing 70 kg varies between 1, 05 μg and 10.50 g per day, with 10.5 μg / day and 1, 05 g / day being preferable.

The different pharmaceutical compositions of the invention can be administered orally or parenterally according to the different pharmaceutical formulations described in Tables 2-5.

EXAMPLE A

Tablet

Table 2. Pharmaceutical formulation and weight of the active substance plus excipients of a tablet.

EXAMPLE B

Tablet

Table 3. Pharmaceutical formulation and weight of the active substance plus the excipients of a tablet.

EXAMPLE C Capsule

Table 4. Pharmaceutical formulation and weight of the active substance plus the excipients of a capsule.

EXAMPLE D Injectable solution Table 5. Pharmaceutical formulation and amount of active ingredient plus excipients of an injectable solution.

Description of Figure 1.

Figure 1 shows the concentration-response curves of the inhibitory effects produced by compound 13 and selegiline on the enzymatic activity of human recombinant MAO-B. Each point represents the mean ± eem (indicated by vertical lines) of five experiments. These results show that compound 13 and selegiline inhibited the enzyme activity of human recombinant MAO-B in a concentration-dependent manner. The examples provided below should be considered for a better understanding of the present invention, without limiting it.

Example 1. Preparation of 6-raethyl-3- (3 ', 5'-dimethoxy) phenylcoumarin (3). A solution of 2-hydroxy-5-methylbenzaldehyde (1.0 g, 7.43 mmol), 3,5-dimethoxyphenylacetic acid (1.80 g,

9.18 mmol) and DCC (2.36 g, 14.32 mmol) in DMSO (20 mL) was stirred and refluxed for 48 hours. After completion of the reaction, ice was added to the cold solution and acidified with acetic acid while stirring for 2 hours.

The solution was extracted with ether (3x25 mL), washed with a 5% sodium bicarbonate solution and then with water. The organic solution was dried over Na ₂ SO ₄ and concentrated in vacuo. The solid residue obtained was purified by chromatography on silica gel using hexane / ethyl acetate (9: 1) as eluent, obtaining 3 with 60% yield.

Mp: 110-1 1 1 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 2.40 (s, 3 H, -CH ₃ ), 3.82 (s, 6H, - OCH ₃ ), 6.50 (t, 1H , H-4 ', J = 2.10 Hz), 6.83 (d, 2H, H-2' and H-6 ', J = 2.10 Hz), 7.22-7.33 (m, 3H, H-5, H-7 and H-8), 7.74 (s, 1 H, H-4).

Example 2. Preparation of 6-methyl-3- (3 ', 4', 5'-triniethox!) Phenylcoumarin (4). It was obtained following the same procedure described for 3 and substituting 3-5-dimethoxyphenylacetic acid for the corresponding 3,4,5-trimethoxypheneacetic acid. obtaining 4 with 72% yield. Mp: 165-166 ° C. ¹ H NMR (CDCl ₃ ) δ (ppin), J (Hz) 2.43 (s, 3H, -CH ₃ ), 3.90 (s, 3H, -

OCH ₃ ), 3.92 (s, 6H, - (OCH ₃ ) ₂ ), 6.93 (d, 2H, H-2 'and H-6', J = 2.10 Hz), 7.24- 7.35 (m, 3H, H-5, H-7 and H-8), 7.76 (s, IH, H-4).

Example 3. Preparation of 3- (4'-hydroxy) feπiI-6-methy-coumarin (5): It was obtained from 6-methyl-3- (4'-methoxy) phenylcoumarin (0.3 g, 1, 13 mmol) [Iridian J. Chem., Sect. B ₁ 35, 1159-62 (1996)] which was dissolved in a mixture of acetic acid / acetic anhydride (1: 1.5mL) cooled to 0 ° C and then 57% iohydric acid in aqueous solution was added slowly. Once the addition was finished, the reaction mixture was refluxed for 24 hours. After the reaction, the solvent is removed and purified by crystallization in aceton &'methanol, obtaining 5 with a 25% yield. Mp: 217-219 ° C. ¹ H NMR (DMSO) δ (ppm), J (Hz) 2.37 (s, 3H, -CH ₃ ), 6.84 (d, 2H, H-

3 'and H-5', J = 8.8 Hz), 7.31 (d, 1H, H-8, J = 8.4 Hz), 7.40 (dd, 1H, H-7, J = 1, 9 and 8.4 Hz), 7.53-7.59 (ra, 3H, H-2 ', H-4', H-5 '), 8.06 (s, 1H, H-4). Example 4. Preparation of 6-cIoro-3- (2'-hydroxy) fenücumariiia (6): Following the procedure described for obtaining 5, from 6-chloro-3- (2'-methoxy) phemlcumarine was obtained 6 with a 35% yield.

Mp: 222-224 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 7.06 (m, 2H), 7.30 (m, 3H), 7.71 (m, 1 H), 7.80 (d, IR J = 2.2), 7.86 (s, 1 H).

Example 5. Preparation of 6-chloro-3- (3'-hydroxy) phenylcoumarin (7); Following the procedure described for obtaining 5, from 6-citoro-3- (3'-methoxy) phenylcoumarin, 7 was obtained with a 38% yield.

Mp: 220-222 ° C. ¹ H RJvIN (CDCl ₃ ) δ (ppm), J (Hz) 6.90 (dd, 1H, J = 2.4 and 7.7), 7.20 (m, 2H), 7.32 (m, 2H), 7.50 (dd, 1 H, J = 2.4 and 8.8), 7.55 (d, 1 H, J - 2.4), 7.78 (s, 1 H).

Example 6. Preparation of 6-chloro-3- (4'-hydroxy) phenylcoumarin (8): Following the procedure described for obtaining 5, from 6-chloro-3- (4'-methoxy-jimml-coumarin, 8 was obtained with 41% yield.

Mp: 240-242 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 6.91 (d, 2H, J = 8.7), 7.30 (d, IH, J = 8.6), 7.47 ( m, 2H), 7.62 (d, 2H, J = 8.7). 7.67 (s, 1 H).

Example 7. Preparation of 6-broroo-3- (2'-hydroxy) phenylcumarIQa (9); Following the procedure described for obtaining 5, from 6-bromo-3- (2'-methoxyijphenyl coumarin, 9 was obtained with a 39% yield.

Mp: 226-228 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 7.07 (m, 2H), 7.35 (m, 3H), 7.69 (m, iH), 7.76 (d, 1H , J = 2.3). 7.85 (s, 1 H).

Example 8. Preparation of 6-bromo-3- (3'-hydroxy) phenylcoumarin (10): Following the procedure described for the preparation of 5, from 6-bromo-3- (3 ^'- methoxy) fentlcumarina was obtained 10 with a 32% yield.

Mp: 217-219 ° C. ¹ H NMR (CDCl.,) Δ (pprn), J (Hz) 6.90 (dd, IH, J = 2.4 and 8.1 Hz), 7.15 (m, 2H), 7.30 ( m, 2H), 7.63 (dd, 1 H, J = 2.3 and 8.8), 7.70 (d, 1H, J-2.3), 7.77 (s, IH).

Example 9. Preparation of 6-bromo-3- (4'-hydroxy) fenHcumarine (11). ' Following the procedure described for obtaining 5, from 6-bromo-3- (4'-methoxy) phenylcoumarin, 11 was obtained in 40% yield.

Mp: 215-217 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 6.92 (d, 2H, J = 8.8), 7.23 (d, 1H, J * 8.5). 7.57 (m, 1 H), 7.62 (d, 2H, J = 8.8), 7.66 (m, 2H).

Example 10. Preparation of 6-brornomethyl-3-phenylcoumarin (12); A solution of 3- phenyl-6-methylcoumarin (1.64 g, 6.94 mmol), N-bromosuccinimide (1.482 g, 8.33 mmol) and a catalytic amount of AlBN in CCU (30 mL) was maintained with stirring and reflux for 18 hours After completion of the reaction, the solution was filtered and the filtrate was concentrated in vacuo and purified by column chromatography on silica gel using hexane / ethyl acetate (9: 1) as a eiudent, obtaining 12 in 46% yield.

Mp: 174-176 ° C. ¹ H NMR (CDCl ₃ ) δ (pprn), J (Hz) 4.56 (s, 2H, -CH ₂ ), 7.35 (d. 2H, J = 8.21), 7.43 (m, 2H). 7.51 (dd, 2H, J- 2.18; 8.21), 7.65 (m, 2H), 7.79 (s, 1H). Example 11. Preparation of 3- (3'-bromo-4'-n »ethoxy) phenyl-6-methylcurnaπna (13);

Following the procedure described for obtaining 12, from 6-methyl-3- (4'-methoxy) phenylcoumarin (2.0 g. 12.5 mmol), N-bromosuccinimide (2.7 g, 15.0 mmo!) and a catalytic amount of AIBN in CCl ₄ was obtained 13 with 41% yield.

Mp: 206-207 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm). J (Hz) 2.42 (s, 3H, -CH ₃ ), 3.94 (s, 3H, - OCH ₃ ), 6.97 (d. 1H, H-5 ', J- 8.7 Hz), 7 , 23-7.35 (m, 3H, H-2 ', H-6' and H-5), 7.71 (m, 2H, H-7 and H-8), 7.89 (d, IH, H -4, J - 3.4 Hz).

Example 12. Preparation of 8-broπio-3-fenH-6-itiethylcuraarine (14): A solution of 2-hydroxy-5-methylbenzaldehyde (0.2 g, 1.5 mmol), NBS (0.314 g. 1.8 mmol) and a catalytic amount of AIBN in CCI ₄ (5 mL) was refluxed for 24 hours. Excess NBS is removed by hot filtration. Upon cooling the filtered solution, a solid precipitates which is purified by column chromatography on silica gel using hexane / ethyl acetate (9: 1) as a binder. The 3-bromo-2-hydroxy-5-methylbenzaldehyde thus obtained is used for the synthesis of 14 following the procedure described below: A solution of 3-brorno-2-hydroxy-5-methylben2; alderudo (1.0 g. 7.43 mmol), phenylacetic acid (1.80 g, 9.18 mmol) and DCC (2.36 g, 14.32 mmol) in DMSO (20 mL) was stirred and refluxed for 48 hours. After completion of the reaction, ice was added to the cold solution and acidified with acetic acid while stirring for 2 hours. The solution was extracted with ether (3x25 mL). it was washed with a 5% sodium bicarbonate solution and then with water. The organic solution was dried over Na ₂ SO, * and concentrated in vacuo. The solid residue obtained was purified by chromatography on silica gel using hexane / ethyl acetate (9: 1) as a binder to obtain 14 in 45% yield.

Mp: 158-160 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 2.41 (s, 3H, -CH ₃ ), 7.27 (d, 1H. J = 2.3 Hz, H-7), 7 , 43-7.47 (m, 3H, H-3 \ H-4 ', H-5'). 7.57 (m. 1H, H-5), 7.68-7.71 (m, 3H, H-4, H-2 'and H-6'). Example 13. Preparation of 8-bromo-6-metii-3- (4'-methoxy) phenylchlormarine (15):

Following the procedure described for obtaining 14, from 3-bromo-2-hydroxy-5- methylbenzaldehyde (0.25 g, 1.16 mmol), 4-methoxyphenylacetic acid (0.241 g, 1.45 mmol) and DCC ( 0.374 g, 1.81 mmol) 15 was obtained in 47% yield. Mp: 144-146 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 2.41 (s, 3H ₁ -CH ₃ ), 3.86 (s, 3H, -

OCHj), 6.98 (d, 2H, H-3 'and H-5', J = 7.1 Hz), 7.26 (s, 1H, H-7), 7.56 (s, 1H, H-5), 7.65-7.69 (m, 3H, H-2 ', H-6 ^! And H-4).

Example 14. Preparation of 8-bromo-6-methyl-3- (3 ', 5'-dimethoxy) phenylcoumarin (16): Following the procedure described for obtaining 14, from 3-bromo-2-hydroxy- 5- methylbenzaldehyde (0.25 g, 1.16 mmol), 3,5-diraethoxyphenylacetic acid (0.285 g, 1.45 mmol) and DCC (0.374 g, 1.81 mmol) 16 was obtained in 46% yield .

Mp: 165-167 ^υ C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz) 2.40 (s, 3H, -CH ₃ ), 3.83 (s, 6H, (- OCHs) ₂ ), 6.52 (t, 1H, H-4 ', J = 2.3 Hz), 6.83 (d, 2H, H-2' and H-6 '), 7.26 (s, 1H, H-7), 7.57 (s, 1H, H-5), 7.70 (s, 1H, H-4).

The following compounds were prepared following reactions known in the organic chemistry sector, by obvious procedures for a person skilled in the art, from known or commercial substances.

Example 15. 6-H¡drox¡-3- (4'-methylphenyl) coumarin (17). PF: 214-215 ° C. ¹ O NMR (DMSO-4,) δ (ppm), J (Hz): 2.32 (s, 3H, -CH ₃ ), 7.01 (d. 1H, H-7, 7 = 8.82, J-2, 87), 7.07 (d, 1H, H-5, J = 2.79), 7.24 (m, 3H, H-3 ', H-5', H-8), 7.59 (d, 2H, H-2 ', H-6', J = 8, 10), 8.08 (s, IH, H-4), 9.77 (s, IH, -OH).

Example 16. 3- (4'-Bromophenyl) -6-hydroxycoumarin (18). PF: 224-225 ° C 1 H NMR (DMSO-d ₆ ) δ (ppm), J (Hz): 7.04-7.13 (m, 2H, H-5, H-8), 7.30 (dd, 1H, H- 7, J = 8.75, J = 2.60), 7.63-7.74 (m, 4H, H-2 ', H-3', H-5 ', H-6'), 8.24 (s, IH, H-4), 9.82 (s, 1H, - OH).

Example 17. 3- (2'-Bromo-3 ', 5'-diomethoxyphenyl) -6-methylcumañna (19). MP: 178-179 ° C 1H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.40 (s, 3H, -CH ₃ ), 3.79 (s, 3H, -OCH ₃ ), 3.87 (s, 3H , - OCH ₃ ), 6.51 (s, 2H, H-4 ', H-6'). 7.30 (m, 311, H-5, H-7, H-8), 7.60 (s, IH, H-4).

Example 18. 6-Methyl-3- (3'-methylphenyl) coumarin (20). MP: 167-168 ° C 1 H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.40 (s, 3H, -CH ₃ ), 3.83 (s, 3H, -OCH ₃ ), 3.90 (d, 6H , - (OCHj) ₂ , J = 96), 6.72 (s, 1H, H-6 '), 7.25 (d, IH, H-8, 7 = 8.4), 7.29 (s, IH, H-5 ), 7.34 (dd, 1H, H-7, J = 8.4, J = 2.0), 7.63 (s, IH, H-4).

Example 19. 6-Methyl-3- (2 ', 4'-dimethoxyphenyl) cimarimarine (21). PF: 154-155 ° C ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.40 (s, 3H, -CH ₃ ), 3.82 (d. 6H, - (OCH ₃ J ₂ , J = I 1.72), 6.56

(dd. 2H, H-3 ', H-5', J-7.03, J = 2.35), 7.28 (m, 4H, H-5, H-6 ', H-7, H-8 ), 7.67 (s, 1H, H-4).

Example 20. 3- (2'-Bromofeni!) - 6-Methylcumarine (22). MP: 141-142 ° C 1H NMR (CDCI ₃ ) δ (ppm), J (Hz): 2.45 (s, 3H, CH ₃ ), 7.28 (m, 1H, H-4 '); 7.35 (m, 211, H-7, H-8); 7.40 (m, 3H, H-5, H-5 ', H-6 ^' ): 7.69 (d, I H. H-3 '); 7.71 (s, 1H, H-4).

Example 21. 6-Methyl-3- (3'-methoxyphenyl) coumarin (23). PF: 84-85 ^U C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.44 (s, 3H, -CH ₃ ), 3.88 (s, 3H, -OCH ₃ ), 6.97 (m, 1H, H- 4 ') , 7.26-7.42 (m, 6H, H-5, H-7, H-8, H-2 ', H-5', H-6 ') 7.78 (s, 1H, H-4).

Example 22. 3- (3'-Hydroxyphenyl) -6-methylcumarine (24). PF: 160-161 ^U C

¹ H NMR (DMSO - * / *) δ (ppm), J (Hz): 2.32 (s, 3H, -CH _? ), 6.77 (dd, IH, H-4 ', J = 7.08, J- 2.42), 7.07 (m, 2H, H-5, H-8), 7.23 (m, 2H, H-5 ', H-6'), 7.38 (dd, 1H, H-7, J = 8 , 46, J- 1, 78), 7.50 (s, 1H, H-2 '), 8.08 (s, 1H, H-4) _> 9.52 (s, IH ₅ -OH). Example 23. 6-Methyl-3- (2'-methoxyphenyl) coumarin (25). PF: 177-178 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.41 (s, 3H, -CH ₃ ), 3.82 (s, 3H, -OCH ₃ ). 7.02 (m, 2H, H- 3 ', H-4 ¹ ), 7.24-7.41 (m, 6H, H-5, H-7, H-8. H-5', H-6 ') 7.69 (s , IH, H-4). Example 24. 3- (2'-Hydroxyphenyl) -6-methymarine (26).

PF: 367-168 ° C

¹ H NMR (DMSO-d ₆ ) δ (ppm), J (Hz): 2.38 (s, 3H, -CH ₃ ), 6.33 (m, 2H, H-3 ', H-5 ¹ ), 7.24 (m , IH, H-5), 7.23 (m, 2H, H-4 ', H-6'). 7.34 (d, IH, H-8. J-8.42), 7.44 (dd, 1H, H-7, J = 8.40, J- 1, 53), 7.97 (s. 1 H, H-4 ), 9.60 (s, 1 H. -OH).

Example 25. S - ^ '- Bromophenyl) -6-methylcoumarin (27). PF: 159-16O ° C

¹ H NMR (CDCl ₅ ) δ (ppm), J (Hz): 2.45 (s, 3H, -CH ₃ ), 7.30 (m, 2H, H-7, H-8), 7.36 (na, 2H, H -5, H-5 '). 7.56 (m. IH, H-4 '). 7.68 (m, IH, H-6 '), 7.80 (s, 1H, H-2'), 7.86 (s, IH, H-4). Example 26. 3- (4'-Bromophenyl) -6-methylcuraarine (28).

PF: 197-198 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.44 (s. 3H, -CH ₃ ), 7.27 (m, IH, H-7), 7.36 (d, 2H, H-5, H -8, J = 7.94), 7.59 (t, 4H. H-2 ¹ , H-3 ', H-5 ^* , H-6'). 7.78 (s, 1H, H-4).

Example 27. 6-Bromo-3-phenyl-8-methoxycoumarin (29). PF: 153-154 ° C. ¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 3.97 (s, 3H, -OCH ₃ ), 7.16 (d, 1H, H-7, J = 2.02), 7.26 (d,

1H, H-5, J-1.97), 7.46 (m, 3H, H-3 ', H-4', H-5 '). 7.70 (m. 3H, H-2 ', H-6', H-4).

Example 28. 6-Bromo-3-methoxyphene-8-methoxycoumarin (30). PF: 183-184 ° C 1H NMR (CDC] ₃ ) δ (ppm), J (Hz): 3.85 (s. 3H, OCH,), 3.96 (s, 3H, OCH ₃ ), 6.95 (m, 2H, H3 ', H5'), 7.12 (d, 1H, H7, J = 1, 76), 7.23 (dd, 1H, H5, 7-2.06, 7-0.88), 7.65 (m, 3H, H4 , H2MI6 ')

Example 29. 6-Bromo-3-methylphenyl-8-methoxycoumarin (31). PF: 164-165 ° C 1H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.40 (s, 3H. -CH ₃ ), 3.98 (s, 3H, -OCH ₃ ), 7.15 (s, IH , H-7), 7.26 (m, 3H, H-3 ', H-5', H-5), 7.61 (d, 2H, H-2 ', H-6', J = 8.23), 7.67 ( s, 1H, H-4).

Example 30. 3- (4'-Bromo-3'-methoxyphenyl) -6-methylcumarine (32). PF: 139-14O ° C.

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 3.91 (s, 3H, -CH ₃ ), 4.60 (s, 3H, -OCH ₃ ), 7.00 (dd, 1H, H- 7, J = 7.38, J = 1.27), 7.30 (m, 2H, H-2 ', H-6', H-8), 7.6 (m, 2H. H-5, H-5 '), 7.84 (s, IH, H-4).

Example 31. 3- (5'-Bromo-2 ', 4'-d-methoxyphenyl) -6-methyl coumarin (33). PF: 208-209 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.43 (s, 3H, -CH ₃ ), 3.86 (s, 3H, -OCH ₃ ), 3.96 (s, 3H, - OCH ₃ ), 6.58 (s, 1H, H-3 '), 7.29 (s, 3H. H-5, H-7, H-8), 7.54 (s, 1H, H-6'), 7.66 (s, 1H, H -4). Example 32. 6-Methyl-3- (3'-methenyl) coumarin (34).

PF: 84-85 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.40 (s, 6H, - (CH ₃ ),)), 7.26 (m, 5H, H-5, H-7, H-8. H-4 ',

H-5 '), 7.60 (d. 2H, H-2', H-6 ', J = 8.2), 7.72 (s, 1H, H-4).

Example 33. 3- (3'-Bromophenyl) -6-methoxycoumarin (35). PF: 151-152 ° C

¹ H PMN (CDCl ₃ ) δ (ppm), J (Hz): 3.91 (s, 3H, -CH ₃ ), 7.02 (d, 1H, H-5, J = 2.90), 7.17 (dd ,

1 HOUR. H-7, J = 9.04, J = 2.96), 7.34 (dd, 2H, H-8, H-5 ', J = 8.96, J = 4.85), 7.57 (m, 1H. H -4 '), 7.70

(m, 1H, H-6 '), 7.82 (s, 1 H, H-2'), 7.78 (s, 1H, H-4).

Example 34. 3- (3'-Bromophenyl) -6-hydroxycunaarin (36). PF: 219-220 ° C

¹ H NMR (DMSO-d ₆ ) δ (ppm), J (Hz): 7.06 (m. 2H. H-5, H-8), 7.28 (d, 1H. H-7, 7-8.89),

7.42 (m, 1H, H-4 '), 7.61 (d, IH, H-5', 7-8.00), 7.73 (d, 1H, H-6 ', 7 = 7.79), 7.93 ( s, 1H, H-2 '),

8.26 (s, 1H, H-4), 9.80 (s, 1H, -OH).

Example 35. 6- (2-Acetonyloxy) -3- (4'-bronaophenyl) coumarin (37). PF: 157-158 ° C ¹ H NMR (CDCI ₃ ) δ (ppm), J (Hz): 2.35 (s, 3H, -CH ₃ ), 4.66 (s, 2H _; -CH ₂ ), 6.98 (d, IH, H-5,

7 = 2.88), 7.20 (dd, 1H, H-7, J = 9.07, 7-2.98), 7.30 (d, 1H, H-8, 7-9.07), 7.61 (rn , 4H, H-2 ', H-3', H-5 ', H-6') _; 7.79 (s, IH, H-4).

Example 36. 6- (2-Acetonyloxy) -3- (4'-methylphenyl) coumarin (38). PF: 128-129 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 2.33 (s, 3H, -CH ₃ ), 2.42 (s, 3H, -CH ₃ ), 4.64 (s, 3H, (- CH ₂ ) , 6.96 (d, IH, H-5, 7-2.93), 7.14 (dd, 1H, H-7, J = 9.05, 7 = 2.98), 7.30 (m, 3H, H-3 ', H-5', H-8), 7.62 (m, 2H, H-2 ', 11-6'), 7.74 (s, IH, H-4).

Example 37. 6-Methyl-3- | 3 '- (2-oxopropoxyphenyl)] coumarin (39). PF: 107-108 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), 7 (Hz): 2.31 (s, 3H, (-CH ₃ ), 2.43 (s, 3H, (-CH ₃ ), 4.61 (s, 2H, - CH ₂ ), 6.94 (d, IH ₁ H-5, J = 1, 23), 7.24-7.42 (m, 6H, H-7, H-8, H-2 ', H-4', H-5 ', H-6 '), 7.77 (s, IH, H-4).

Example 38. 6- (2-acetonyloxy) -3- (3'-bromophenyl) coumarin (40). PF: 167-168 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (H ?.): 2.30 (s, 3H, (-CH ₃ ), 4.6! (S, 3H, (-CH ₂ ), 6.94 (d, 1H, H-5, J = 3.03), 7.15 (dd, IH, H-7, J = 9.10, J = 2.04), 7.33 (dd, 2H, H-5 \ H-8, ./ -8.09, J = 2.36), 7.53 (m, 1H, H-4 '), 7.66 (m, IH, H-6'), 7.75 (s, 1H, H-2 '). 7.83 ( s, 1H, H-4).

Example 39. 6-Cyclopentyloxy-3- (4'-raethylphenyl) coumarin (41). PF: 147-148 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 1.37-1.9 (m, 8H, (-CH ₂ ) ₄ ), 2.52 (s, 3H, -CH ₃ ), 4.89 (s, 1H, HI "), 7.05 (d, IH, H-5), 7.17 (dd, 1H, H-7, J = 8.99, J = 2.74), 7.38 (m, 3H, H-3 ', H -5 ', H-8), 7.72 (d, 2H, H-2', H-6 ', J = 8.11), 7.84 (s, 1H, H-4).

Example 40. 3- (4'-bromophenyl) -6-cyclopentyloxycoupiarin (42). PF: 164-165 ° C

¹ H NMR (CDCI ₃ ) δ (ppm), J (Hz): 1.27-1.41 (m, 4H, H-3 ", H-4"), 3.49-1.72 (m, 2H, H-5 "), 1.77-2.29 (m, 2H, H-2 "), 4.38 (m. IH, HI"), 6.96 (d, 1H, H-7, 7-2.69), 7.15 (m, 2H, H-5, H -8), 7.2-7.38 (m, 2H, H-2 ', H-6') 7.44-7.67 (m, 2H, H-3 ', H-5'), 7.76 (s, IH, H-4 ).

Example 41. 3- (3'-bromophenyl) -6-cycloopentyloxycoumarin (43). PF: 228-229 ° C

¹ H NMR (CDCl ₃ ) δ (ppm), J (Hz): 1.57-1.99 (m, 9R H-1 ", H-2 ¹ ', H-3", H-4 ", H-5") , 6.95 (d, 2H, H-7, 7-3.04), 7.05 (m, 2H, H-5, H-8), 7.24-7.35 (m, 2H, H-4 ', H-6' ), 7.53 (m, IH, H- 5 '), 7.76 (s, 1 H, H-2-), 7.84 (s, 1 H, H-4).

Claims

1. Use of a compound of formula I, for the preparation of a medicament for treating disorders derived from the hyperactivity of the MAO-B isoform,

where,

R2 ', R3', R4 ', R5' and R6 'are identical or different, each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkyloxy, acyloxy, acyl or nitro,

R4 is hydrogen, R5. R7 and R8 are identical or different, each independently selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkyloxy, acyloxy, acyl, aethylmethoxy, alkylsulfonyloxy, arylsulfonyloxy or nitro,

R6 is selected from halogen, alkyl, haloalkyl, alkyloxy, acyloxy. acyl, aethylmethoxy, alkylsulfonyloxy, arylsulfonyloxy or nitro.

2. Use of a compound of formula 1, according to claim 1, wherein R2 ', R3', R4 ', R5' and R6 'are identical or different, each independently selected from hydrogen, halogen, hydroxyl, or alkyloxy.

3. Use of a compound of formula I according to the preceding claims, wherein R6 is halogen, alkyl or haloalkyl.

4. Use of a compound of formula I according to claim 1, wherein

R6 is alkyl or alkyloxy, preferably methyl or methyloxy.

5. Use of a compound of formula I according to the preceding claims, selected from: (1) 3-phenyl-6-methyl coumarin

(2) 6-methyl-3- (4 '-methoxy) femlcυmarina

(3) 6-methyl-3- (3 ', 5' -dimethoxy) phenylcwnarine

(4) 6-meti! '3- (3', 4 ', 5' -trimethoxy) phenylcoumarin

(5) 3- (4'-Hydroxy) phenyl-6-methicumarine (6) 6-chloro-3- (2'-hydroxy) phenylcoumarin

(7) 6-chlorθ'3- (3'-hydroxy) phenylcιιmarine

(8) 6-Chloro-3- (4'-hydroxy) phenylcoumarin

(9) 6-bromυ-3- (2'-hydroxy) phenylcoumarin

(10) 6-brυmo-3- (3 '-hydroxy) phenylcιιmarin (1 1) 6-bromo-3- (4' -hydroxyijfenfilcumarine (12) 6-bwmomethyl-3-phenylcumariiia

(13) 3- (3 '-bromo-4' -methoxy) phenyl-6-methylcumarma

(14) 8-Bromo-3-phenyl-6-methylcoumarin

(15) H-bromυ-6-methyl-3- (4 '-methoxy) phenylcoumarin (16) 8-bromo-6-meül-3- (3', 5 '-dimethoxyjfeni [amarina

(27) 3- (3 '-bromo) phenyl-6 methylcoumarin

(28) 3- (4'-bromine) phenyl-6 methylcoumarin (35) 3- (3'-bromine) phenyl-6 methoxycoumarin

6. Use according to the preceding claims, wherein the disorders derived from the hyperactivity of the MAO-B isoform are degenerative disorders of the central nervous system or obesity.

7. Use according to claim 5, wherein the degenerative disorders to be treated are Parkinson's, Alzheimer's, schizophrenia, senile dementia or ataxia.

8. A pharmaceutical composition comprising a compound of formula 1 as described in claims 1 and a pharmaceutically acceptable carrier.

9. A compound of formula I, as defined in claim 1, wherein R3 'and R4' at least one of them is halogen and the other is selected from hydrogen and alkyloxy.

R4, R5, R7, R8, R2 ', R5'and R6' are hydrogen,

R6 is alkyl or alkyloxύ preferably methyl or methyloxy.

10. A compound of formula I. as defined in claim 1, selected from:

6-methyl-3- (3 ', 5' -dimethoxy) phenylcoumarin (3)

6-metü-3- (3 '.4', 5 '-trimethoxy) fenucumarine (4)

3- (4'-hydroxy) phenyl-6-methylcoumarin (5) 6-chloro-3- (3'-hydroxy) phenylcoumarin (7)

6-Bromo-3- (3-hydroxy) phenylcumarine (JO)

6-Bromo-3- (4 '-hydroxy) phemlcumarin (11)

6-bromomethyl-3-phenylcoumarin (12)

3- (3 '-bromo-4' -rnethoxy) phenyl-6-methylcoumarin (13) 8- bromo- 3-phenyl-6-methylcumarma (14)

8-Bromo-6-methyl-3- (4'-methoxy) phenylcoumarin (15)

8-Bromo-6-methyl-3- (3 ', 5' -dimethoxy) phenylcumarma (16)

3- (3 '-bromo) phenyl-6 mctylcumωϊna (27)

3- (4 '-bromo) feni¡-6 methylcoumarin (28) 3- (3' -bromo) phenyl-6 methoxycoumarin (35)

1 1. A process for obtaining a compound of formula I, as described in claim 1 selected from those wherein one between R3 'or R8 is halogen, consisting of a) bromination of a compound of formula II

27

b) Perkin reaction between a compound of formula U and a compound of formula FIl, wherein R5, R6, R7, R8, R2 ', R3', R4 'and R5' are as described in claim 1.

12. A process for obtaining a compound of formula I. as described in claim 1 selected from those wherein R 6 is haloalkyl, which consists of brominating a compound of formula I wherein R 6 is alkyl.